A Systematic Review of Acute Thoracic Aortic Dissections in Africa—The Need for a Registry

In this systematic review, the available literature on the presentation and management of acute thoracic aortic dissections in Africa is examined. Though Africa has 17% of the world population, it accounts for approximately 1% of the available literature with much of our understanding coming from registries arising from the developed world, such as the International Registry of Acute Aortic Dissection. The literature from the African continent consists mainly of case reports, small case series, and few original studies. Case reports make an important contribution to our understanding of uncommon conditions but can skew our understanding of aortic dissections in this region by describing unusual presentations and management. In this review, we describe the available studies retrieved from large medical databases (Medline and Health Management Information Consortium) and motivate the need for national registries to provide a more accurate appreciation of the scope of the problem on this continent.


Introduction
Acute thoracic aortic dissections are relatively rare with an estimated incidence of 2.53 per 100,000 but with high morbidity and mortality. 1 Presentations can vary from chest, back, or abdominal pain; syncope; organ malperfusion syndromes; to cardiac tamponade and death. 2 Aortic dissections have a long history with the first fully described case being the sudden death of King George II of Great Britain in 1760. Meaningful treatment for this condition was only developed in the 1950s and 1960s with the pioneering work of the famed cardiothoracic surgeons, DeBakey et al. 3,4 Our understanding of aortic dissections has grown over the past two to three decades: Clinicians appreciate the importance of early surgery with ascending aortic dissections and the role of endovascular stenting in descending aortic dissections (where medical management was previously the standard of care). In addition, we have a better grasp of the role of inherited connective tissue disorders including Marfan's, Ehler's-Danlos, and the Loeys-Dietz syndromes and the genetics involved in nonsyndromic, familial aortic dissections. 5,6 The knowledge gained is helping physicians prevent dissections in at-risk populations. Imaging modalities and Keywords ► thoracic aortic dissections ► Type Stanford A dissection ► Type Stanford B dissection ► Africa

Abstract
In this systematic review, the available literature on the presentation and management of acute thoracic aortic dissections in Africa is examined. Though Africa has 17% of the world population, it accounts for approximately 1% of the available literature with much of our understanding coming from registries arising from the developed world, such as the International Registry of Acute Aortic Dissection. The literature from the African continent consists mainly of case reports, small case series, and few original studies. Case reports make an important contribution to our understanding of uncommon conditions but can skew our understanding of aortic dissections in this region by describing unusual presentations and management. In this review, we describe the available studies retrieved from large medical databases (Medline and Health Management Information Consortium) and motivate the need for national registries to provide a more accurate appreciation of the scope of the problem on this continent. guidelines on measurements are improving and becoming more standardized. 7 From the emerging genetic data, dedicated aortic centers are refining surgical guidelines to prevent dissections in patients with high-risk genes. 5,8 Recommended aortic diameters at which prophylactic surgery is offered are tailored to one's genetic profile. 8 Even the use of aortic diameter alone as a measure of risk is being challenged by examining the role of aortic wall thickness. 9 Many of our insights on aortic dissections, which have improved our understanding and management of this disease, have come from large multinational registries such as the International Registry of Aortic Dissection (IRAD) which is now over 20 years old. 10 It is a large registry including over 7,300 patients from around 51 centers from 12 countries from North America, Europe, Asia, and Australasia (iradonline.org). Similarly, the Nordic Consortium for acute Type A aortic dissections includes eight centers from the Nordic countries of Denmark, Finland, Iceland, and Sweden. 11 Despite the value of these registries, it is noticeable that they do not include any centers from the African continent. This gap in our understanding of how aortic dissections present and are managed in Africa needs to be addressed.

Objectives
The purpose of this systematic review was to facilitate our understanding of how acute thoracic aortic dissections present and are managed in South Africa and the rest of Africa.
We aimed to address the following questions on the presentation of this condition: • What are the most common symptoms and clinical signs on presentation? • What are the underlying etiologies described-are they different from what is described in the international literature? • Do patients present later? • How have patients been managed-is there a greater use of medical therapy versus surgery because of resource limitations?
We audited the available literature on the management of aortic dissections in Africa to determine whether it addressed the following issues: • Surgery versus medical management. 12 • Open surgery versus endovascular stenting. 13,14 • β blockers versus other antihypertensive agents. 15 • The use of angiotensin receptor blockers versus other antihypertensives (there has been speculation that the angiotensin II receptor blockers losartan reduces the expression of transforming growth factor β which has been implicated in the growth of aneurysms). 16

Materials and Methods
A systematic review was initiated in October 2020. The intention was to evaluate available clinical studies and perform a meta-analysis, if appropriate, on the management of acute thoracic aortic dissections in Africa. The review was conducted following the principles outlined in the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines 17 by two independent doctors with clinical insight into the conditions. The established medical databases, PubMed/Medline and Health Management Information Consortium, were used to do a comprehensive literature search on October 31, 2020. Details of the protocol for this systematic review were registered on the International Prospective Register of Systematic Reviews (PROSPERO) and can be accessed at: www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42021268459.
Studies used for the systematic review included only published studies in peer-reviewed journals such as clinical trials, previous systematic reviews, and case reports. Foreign language articles were included. A flow chart depicting the systematic review process is illustrated in ►Fig. 1.
An initial search of the two databases used the key terms mentioned below: This search yielded 13,666 studies in total. Thereafter, the same key terms were used as follows: Twenty-five studies were yielded in combining the databases.
The search was then repeated using the following terms: • Aortic dissection.
• The name of each of the 54 separate countries in Africa as listed by the United Nations (UN.org).
An additional 89 studies were yielded in this third step. Using this strategy, 114 published articles were yielded (►Fig. 1). Duplicate articles, studies that did not originate from an African center, studies of abdominal dissections, animal studies, and book chapters (with oblique references to aortic dissections) were excluded. Only 39 studies originating from African centers, published between 1978 and 2020, were, thus, obtained (►Fig. 1).
From these 39 studies, we further excluded: four letters to the editor, two article reviews (one was a review on the current knowledge and management of aortic dissections not specific to Africa, and a review of chest pain syndromes with an indirect reference to aortic dissections), and a registry of cardiac disease in pregnancy (as the underlying cause of the three patients with aortopathies in African countries was not known). A further six were excluded as only abstracts were available (four were from the now defunct Dakar Medical Journal which stopped publishing in 2008, one was from Tunisia Medicale with articles from their archives before 2004 unavailable, and one from the Moroccan Medical Journal from 1985 was also unavailable).
Of the remaining 26 studies, carried through to the final analysis: • There were five observational studies: three interventional studies (one of surgery in Stanford A patients, 18 one of endovascular stenting in Stanford B patients, 19 and one of cardiac bypass surgery in human immunodeficiency virus [HIV]-positive patients 20 ) and two postmortem studies looking at causes of sudden cardiac death in a general population and among athletes. 21,22 • We included one study which arose from our search of articles from "Africa" which was written by an author from Vanderbilt University in the United States. 23 It was a retrospective record review which looked at the incidence of aortic dissections and aortopathies in 21 regions around the world based on ICD 10 diagnostic codes in records provided. The study included regions in Africa and was the only available article in the literature that provided a global perspective of the incidence of aortic dissection. • There were 20 case reports or case series. [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] Available demographic and clinical data were collected and captured on an Excel Spreadsheet (see ►Fig. 2).
A summary of the five observational studies was tabulated (►Table 1) according to The Strengthening of Observational Studies in Epidemiology (STROBE) recommendations 44 in optimizing the reporting for these types of studies. Similarly, the CARE (Case Report) guidelines 45 for reporting were used as a template in evaluating and tabulating the case reports we included.
Our initial objective was to conduct a meta-analysis of outcomes in both Stanford A and Stanford B dissections using either surgical or medical management, and open surgery or endovascular stenting if the studies had complete and reliable data. Meta-analysis comparing medication regimens used was not possible as data were inhomogeneous. The observational studies of intervention included for analysis were also inhomogeneous and not suitable for meta-analysis. No randomized control trials were found in our search.

Distribution and Types of Studies
Of the 26 studies from African medical centers which were included for analysis, 19 were in English, and seven were in French. Most studies, 20, were case reports, 5 were observational studies (2 of the 5 observational studies were postmortem), and one was a global review which included regions in Africa.

Epidemiology
In these studies, clinical information was often incomplete. The background clinical characteristics were extracted, when available, from the 20 case reports and the five observational studies (►Tables 1,2,3). As studies were not uniform, each characteristic in the Tables is represented according to the number of articles that featured it (►Table 1).
Trends in Africa were in keeping with our current understanding of aortic disease from established registries such as IRAD, with a male preponderance, an association with hypertension, a higher proportion of Stanford A dissections, and chest pain being the most common initial presentation for dissection (►Table 1).
The average age of Stanford A patients was 41.2 years of Stanford B patients was 52.3 years of age, and the average age of total number of patients with thoracic aortic dissections was 47.5 years of age.
Where data were available, patients were predominantly of the Black race and other ethnicities included patients of Arab descent, especially in studies originating from North Africa.
Most of these numbers were not statistically significant. The true incidence of aortic diseases and aortic dissection in Africa, and its individual countries, are not known. But, in the study by Sampson et al 23 from Vanderbilt University, data from the Global Burden of disease study were taken to estimate the incidence of aortic aneurysm-and aortic dissection-related mortality in different regions in the world from 1990, at the time of their initial study, until 2010.
They found that the global mortality rate per 100,000 population had increased from 2.49 to 2.78. In developed countries, the relative increase over the 20 years was the smallest. In comparison, the relative increase in developing countries, which included central Sub-Saharan Africa, was among the greatest. This was despite the low incidence of aortic diseases which was the result of a "paucity of surveillance data" from these regions. The authors postulate that this epidemiological transition in aortic disease patterns may signal potential challenges for the poorly equipped health care systems of the developing world.

Etiology
Hypertension was the most frequently associated underlying cause. Other etiologies reported included connective tissue disorders such as Marfan's syndrome, inflammatory conditions such as Takayasu's arteritis, and the HIV.

Management
From the available case reports, it was surprising that Stanford A dissections were still managed conservatively without urgent surgical intervention. The reasons for this included lack of availability of surgical facilities or surgeons in the admitting center, lack of availability in the country, or rapid deterioration of the patient before surgery.
As expected, Stanford B patients were managed medically. However, one observational study from Egypt included a study group of 24 Stanford B aortic dissection patients that were managed with endovascular aortic replacement (EVAR) in a clinical trial, in a highly specialized center, with good outcomes.

Outcomes
In the Stanford A patients, survival was poor without surgery. The case studies that reported survival without surgical intervention were likely reported because of their rarity.
Even where surgery was offered, the mortality rate was as high as 24%. 18 No Stanford B patients were offered open surgery, and survival to discharge was 60% for those treated with medication alone. The outcomes of endovascular stenting were shown to be favorable in Stanford B dissections where the patient selection was appropriate. 19

Discussion
This systematic review on aortic dissections is, to our knowledge, the first of its kind conducted in Africa. It has shown the lack of data on thoracic aortic dissections from this continent. Though we have attempted to be thorough in our review of available studies in Africa, it is likely that a few studies may have been missed. There are other large medical databases such as EMBASE (which was not used because of availability and costs). Nonetheless, we believe this review is a true representation of the lack of studies on this condition originating in Africa: a continent with almost a fifth of the world's population publishing less than 1% of the literature on aortic dissections.
There may be several reasons for this including financial, hospital resources, lack of expertise, and perhaps, a lower incidence of this condition. Regardless of the reasons, we do not think that the available literature accurately reflects the presentation and management of aortic dissections in Africa.

Publication Bias of Case Reports
The majority of publications were dominated by case reports with few original research articles found from this region. Though randomized controlled trials are the gold standard of clinical studies, it may not be possible to get a sufficient number of subjects over a meaningful period (e.g., 5 years) in relatively rare diseases. Thus, case reports can be invaluable in providing insights into uncommon disorders, at the risk of skewing perceptions due to unusual presentations of this condition.    The experience of the authors from their own institutions in South Africa is that the management of Stanford A and Stanford B dissections are more in line with IRAD data using European and U.S.-based guidelines.

Future Directions and the Need for National Registries
We do not believe that the lack of data in Africa represents a lower incidence of aortic dissections on this continent, but rather an under-reporting of this condition. It is noticeable that IRAD does not include an African center.
There exists a need in Africa to develop a better understanding of how dissections manifest and our management here: • What are the differences in etiology and management?
• Where are the centers of excellence? • How can we improve outcomes?
In the study of uncommon conditions such as aortic dissection, the recruitment of patients for a randomizedcontrolled trial may take a long time and be prohibitively expensive for resource-limited countries. A registry has the potential to be a powerful tool. It allows centers from different countries to pool resources.
In August 2020, a pilot launch of a South African Registry of Acute Aortic Dissections was conducted under the auspices of the South African Cardiothoracic Society. The plan was to create a national registry to better understand and manage this rare but potentially fatal condition. We believe it will provide much needed data and create the environment where centers of excellence may emerge and extend into the rest of Africa.

Limitations
This systematic review was limited by the limited number of studies with often incomplete clinical data. Statistically meaningful conclusions were often not possible, and no definitive conclusions could be drawn. More high-quality, original studies and registry data showing real-world outcomes in Africa are needed.

Conclusion
There is a paucity of data on acute thoracic aortic dissections from Africa, with few original studies. Though Africa has 17% of the world's population, it accounts for less than 1% of the published literature on this topic. There are limited highquality, original articles with a preponderance of case reports.
Though case reports provide useful insights, inherent selection bias may not represent real-world presentation and management on this continent. In a resource-poor region, randomized control trials may be prohibitively expensive and logistically difficult to conduct. National registries may provide the means of pooling useful data across this region for the benefit of patients of this relatively rare but important condition.

Data Analysis
Data available for trials were not found to be sufficiently uniform for pooled analysis.

Ethics
Ethics approval was obtained through the South African Medical Association Research Ethics Committee (SAMAREC) (ethics approval number: SARAD002). This study was conducted in keeping with the principles of the Declaration of Helsinki and in keeping with the recommendations of Good Clinical Practice.

Funding
None.